The extracellular-signal regulated kinases (ERK 1/2) represent an essential component of a signaling cascade that controls a number of fundamental cellular processes and has been established as an attractive target for anti-cancer therapies in broad-spectrum human tumors. GDC-0994 is an orally bioavailable small molecule inhibitor of ERK 1/2 kinase activity. We will present the process development towards a practical, scalable synthesis of GDC-0994 featuring a biocatalytic asymmetric ketone reduction, a continuous palladium-catalyzed Kumada-Corriu cross-coupling, a tungsten-catalyzed sulfide oxidation and an end-game impurity control strategy. Finally, development of the API crystallization allowed for multi-kilogram deliveries of GDC-0994 in &gt;99.5% LCAP and &gt;99% ee to enable clinical trials.<br/>

Development of a practical synthesis of ERK inhibitor GDC-0994

253rd National Meeting (2017)

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